Controlling the immunotransmitter cGAMP with chemical biology
Abstract/Contents
- Abstract
- cGAMP is a second messenger that mediates innate immune response to cancer, infection, and cellular damage. cGAMP synthesis is triggered by a danger signal common to all these pathologies, the presence of DNA in the cytosol. Downstream, cGAMP activates the Stimulator of Interferon Genes (STING) protein which eventually leads to the production of interferon to combat these threats. Originally, cGAMP was thought to function exclusively intracellularly, stuck inside the cell where it was produced. Then, the realization that cGAMP's only hydrolase ENPP1 was extracellular hinted that cGAMP, too, might travel outside of its originating cell. However, the field lacked tools to test this hypothesis. This dissertation builds chemical biology tools and uses them to define and control cGAMP's role as an extracellular immune signal, or immunotransmitter. Chapter 1 contextualizes the role of cGAMP as an immunotransmitter in terms of the entire cGAMP-STING pathway. Chapter 2 demonstrates that cGAMP is constantly exported from cancer cells and activates host anti-cancer immunity. Chapter 3 chronicles the development of best-in-class ENPP1 inhibitors that block extracellular cGAMP degradation, functioning as both chemical tools and investigational cancer drug candidates. Chapter 4 engineers an ENPP1-based tool that selectively enhances extracellular cGAMP in vivo and shows that cGAMP acts as an immunotransmitter in pathologies beyond cancer, including viral infection and cellular damage. Chapter 5 looks ahead to the trajectory of the cGAMP immunotransmitter field. This work pioneers cGAMP's extracellular immunotransmitter role in innate immunity and takes first steps to harness it therapeutically.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Carozza, Jacqueline Ann |
|---|---|
| Degree supervisor | Li, Lingyin |
| Thesis advisor | Li, Lingyin |
| Thesis advisor | Dassama, Laura |
| Thesis advisor | Khosla, Chaitan, 1964- |
| Degree committee member | Dassama, Laura |
| Degree committee member | Khosla, Chaitan, 1964- |
| Associated with | Stanford University, Department of Chemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jacqueline Ann Carozza. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/df532qs5050 |
Access conditions
- Copyright
- © 2021 by Jacqueline Ann Carozza
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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